Linoleic acid improves PIEZO2 dysfunction in a mouse model of Angelman Syndrome

Abstract

Angelman syndrome (AS) is a neurogenetic disorder characterized by intellectual disability and atypical behaviors. AS results from loss of expression of the E3 ubiquitin-protein ligase UBE3A from the maternal allele in neurons. Individuals with AS display impaired coordination, poor balance, and gait ataxia. PIEZO2 is a mechanosensitive ion channel essential for coordination and balance. Here, we report that PIEZO2 activity is reduced in Ube3a deficient male and female mouse sensory neurons, a human Merkel cell carcinoma cell line and female human iPSC-derived sensory neurons with UBE3A knock-down, and de-identified stem cell-derived neurons from individuals with AS. We find that loss of UBE3A decreases actin filaments and reduces PIEZO2 expression and function. A linoleic acid (LA)-enriched diet increases PIEZO2 activity, mechano-excitability, and improves gait in male AS mice. Finally, LA supplementation increases PIEZO2 function in stem cell-derived neurons from individuals with AS. We propose a mechanism whereby loss of UBE3A expression reduces PIEZO2 function and identified a fatty acid that enhances channel activity and ameliorates AS-associated mechano-sensory deficits.

Progressive Irreversible Proprioceptive Piezo2 Channelopathy-Induced Lost Forced Peripheral Oscillatory Synchronization to the Hippocampal Oscillator May Explain the Onset of Amyotrophic Lateral Sclerosis Pathomechanism

“…According to the Piezo2 channelopathy theory, the membrane lipids and cholesterol surrounding Piezo2 could be depleted during excessively prolonged mechanostransduction under allostasis [ 18 , 28 ]. It is indicative of the acquired Piezo2 channelopathy theory and the functional relevance of lipids that the replacement of linoleic acid improves Piezo2 function in a neurodegenerative disease [ 37 ]. It is worthy of note that lipid and cholesterol dyshomeostasis has an often-reported association with ALS, although a controversial one [ 38 ].…”

“…In addition, this atypical hippocampal-like metabotropic PLD-mGluR is homomeric to metabotropic GluK2 [ 37 ], and GluK2 has a role in the maintenance of glucose homeostasis [ 78 ]. Correspondingly, mGluRs and GABA are involved in glucose-stimulated insulin secretion from the beta cells of pancreas [ 79 ] and Piezo1 plays a critical role in this mechanism [ 80 ].…”

Phosphatidic acid is an endogenous negative regulator of PIEZO2 channels and mechanical sensitivity

“…Next, we tested if endogenous PLD activity also regulates PIEZO2 channels in their native environment. First, we performed experiments in human induced pluripotent stem cell (hiPSC)-derived sensory neurons (Anatomic Incorporated) 28 . Consistent with earlier results 28 , these cells displayed predominantly rapidly adapting mechanically-activated currents.…”

“…First, we performed experiments in human induced pluripotent stem cell (hiPSC)-derived sensory neurons (Anatomic Incorporated) 28 . Consistent with earlier results 28 , these cells displayed predominantly rapidly adapting mechanically-activated currents. As shown in Figure 7a , mechanically-activated current amplitudes were significantly higher in FIPI-treated cells, compared to control cells.…”

“…The dietary saturated fatty acid margaric acid (C17:0) has been shown to inhibit both PIEZO1 and PIEZO2 activity, with a higher potency on PIEZO1 17,30 . Linoleic acid (C18:2), an unsaturated dietary fatty acid on the other hand was shown to increase the activity of both PIEZO1 and PIEZO2 28,30 .…”